PROJECT SUMMARY/ABSTRACT Microneedles are a minimally invasive method for enhancing skin permeability through the creation of micropores in the epidermis. The micropores are aqueous pathways that allow an otherwise skin-impermeable drug to pass through the skin and be delivered systemically. This has important implications for the treatment of many diseases in diverse patient populations. Drug delivery parameters (drug formulation, microneedle length/number) and in vivo considerations (rate of closure of the micropores) both contribute to the pharmacokinetics and drug disposition. Despite extensive study of microneedles in humans, there is a large paucity of data describing how physiologic factors such as sex/gender and race/ethnicity affect the drug delivery profile. Many significant differences are present in the skin of subjects of differing sex/gender and race/ethnicity, including variations in epidermal thickness, reactivity, and recovery from insult. Epidermal thickness also varies dramatically between different sites of the body. In order to achieve widespread use of microneedles for drug delivery, it is necessary to understand the variability in drug delivery profiles between diverse patient subgroups. The effect of physiologic factors on the drug delivery profile cannot be predicted from in vitro diffusion studies, which makes it critical to study the in vitro and in vivo settings together. The long- term goal of this research is to develop advanced microneedle delivery platforms that will improve pharmacotherapy and treatment for diverse patient populations with a variety of acute and chronic diseases. The strategy of this 5 year MIRA research program is to make correlations between preclinical drug delivery studies and clinical human microneedle studies by combining fundamental and applied research. In vitro studies will aim to maximize percutaneous flux of macromolecules and small molecules by optimizing formulation and microneedle delivery parameters. We will study micropore closure rates and drug absorption profiles from numerous anatomical sites in healthy human volunteers of differing sex/gender and race/ethnicity. Microneedle length and number, and drug formulation will be studied as additional factors that may contribute to in vivo variability. In the clinical studies we will calculate micropore closure half-lives under various conditions and validate the predictions with pharmacokinetic studies. Correlations will be made between in vitro percutaneous flux studies and in vivo pharmacokinetic studies for each patient population. This MIRA program will expand our understanding of how physiologic variables affect microneedle drug delivery in healthy subjects, and in the future we will expand upon these results and perform micropore closure and pharmacokinetic studies in patients with systemic diseases. This will enable us to understand how diseases further contribute to variation in response to microneedles. We then will have the necessary tools to optimize microneedle delivery in distinct patient subsets for treatment of disease.